Nicotine is a serious health problem that is resistant to treatment for millions of people. In the United States, tobacco use is responsible for about 440,000 deaths per year, and an estimated 49,000 of these tobacco-related deaths are the result of secondhand smoke exposure. Cigarette smoking costs more than $193 billion (i.e., $97 billion in lost productivity plus $96 billion in health care expenditures). Nicotine is one of the most heavily used addictive drugs and accounts for 90% of lung cancer cases in the U.S. Nicotine, the addictive component of tobacco, binds to specialized proteins in the brain, called a5 nicotinic receptors. Evidence suggests that a5 receptors can be a contributing factor in the risk towards smoking dependence, indicating its potential as a therapeutic development strategy for smoking cessation. Common strategies for smoking cessation therapies are to break the reward cycle between smoking and the reward - pleasure - signal that is the typical consequence of nicotine consumption. a5 receptors are located in a brain region that mediates aversion to nicotine, the medial habenula. Activation of the medial habenula can cause reduction of nicotine intake in animal models. This proposal focuses on the development of a drug that activates a5 receptors to help smokers quit smoking. The research performed under this award will transform early stage candidate molecules into drug-like pre-clinical leads. A successful project outcome will be the development of a clinical candidate that can be tested in humans, with the end goal of delivering a smoking cessation drug to the public.